The overall goal of this research is to improve 1) methadone maintenance therapy, the cornerstone of opiate abuse treatment and a vitally effective strategy for HIV/AIDS risk reduction, 2) the safety and effectiveness of methadone when used for pain treatment, and 3) the treatment of HIV/AIDS. Methadone disposition is characterized by unexplained and unpredictable variability, causing opiate withdrawal, toxicity, and treatment failures. Increased methadone use for pain treatment has been accompanied by an epidemic of adverse reactions, particularly in the early weeks of therapy. Highly active antiretroviral therapy for HIV/AIDS causes clinically significant, complex, and insufficiently understood drug interactions. Methadone-anti retroviral drug interactions are clinically significant but poorly understood, and not predictable based on present knowledge. Both pharmacokinetic and pharmacodynamic interactions can occur. The proposed research challenges the longstanding notion that cytochrome P4503A is responsible for clinical methadone metabolism and drug interactions. Antiretroviral interactions which inhibit drug metabolism generally are well understood, however those which up regulate metabolism remain poorly understood. Pharmacodynamic interactions suggest a role for drug transporters in brain methadone disposition, but these transporter(s) are presently unknown. The aims of this research program are to definitively elucidate enzymes and mechanisms of both hepatic and renal methadone clearance, the influence of anti retroviralson the enzymes and transporters mediating methadone disposition, and the role of drug transporters in methadone pharmacodynamics and clinical effects, and the influence of antiretrovirals on those critical pathways. A concerted clinical and translational approach to these aims will be pursued. A series of complementary laboratory-based and clinical studies are planned for each aim, combining novel cellular models of metabolism and transport with comprehensive mechanistically-driven and therapeutically applicable clinical protocols in healthy subjects and patients. Clinical studies will use novel in vivo probes and methods for determining method one brain disposition and pharmacodynamics. Successful completion of the aims will provide fundamental new information on methadone disposition, improve methadone therapeutic guidance and safety, and enhance the treatments and outcomes of opiate addiction, pain and HIV/AIDS. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to the significant public health problems of HIV/AIDS, substance abuse, drug interactions, appropriate treatment of pain, inappropriate use of prescriptionopioid pain medications, and the rising incidence of serious adverse complications from pain treatment. It is also relevant to creating a better basic understanding of how drugs enter the brain and are inactivated by the body, and how therapeutic drugs affect healthy and ill individuals.